IVIG for CAR-T Therapy-Related Hypogammaglobulinemia: Uses, Benefits, Dosage, and More

Clinicians often recommend IVIG for CAR-T therapy-related hypogammaglobulinemia to reduce infection risk and improve survival. However, these recommendations are slim and based on expert opinion and clinical trial results. 

A Quick Overview of CAR-T Therapy

CAR-T therapy is an acronym for chimeric antigen receptor (CAR)-T cell therapy. A form of immunotherapy, CAR-T cell therapy is currently used to treat certain blood cancers. Immunotherapy for cancer enhances your immune system’s ability to identify and destroy cancer cells. 

As the name suggests, CAR-T cell therapy uses the patient’s own T cells. T cells or T lymphocytes are a type of white blood cell that primarily destroy bacteria, viruses, and cancer cells. 

CAR-T cell therapy involves the following steps:

1. T cells are collected from a patient’s blood and sent to the lab. 
2. In the lab, these cells are genetically modified to create special proteins called chimeric antigen receptors (CARs) on the cell surface. 
3. The modified cells — CAR-T cells — are grown to millions in the lab. 
4. Lastly, when there are enough of the modified cells, they are administered to the patient in a single infusion. Once in the patient’s bloodstream, these cells identify and kill cancer cells. 

The entire process, from collection to reinfusion, takes about 4 weeks. 

Examples of FDA-approved CAR-T cell therapy include:

• Yescarta
• Kymriah
• Tecartus
• Carvykti
• Abecma
• Breyanzi

What Is CAR-T Therapy-Related Hypogammaglobulinemia?

Hypogammaglobulinemia is when immunoglobulin G (IgG) levels drop too low, increasing a person’s risk of getting potentially life-threatening bacterial, viral, or fungal infections. 

CAR-T therapy-related hypogammaglobulinemia is common and expected during or after CAR-T therapy. It can occur a few weeks after infusion and last months or even years. Studies show that children are more likely than adults to get CAR-T therapy-related hypogammaglobulinemia [1].

The definitions of CAR-T therapy-related hypogammaglobulinemia can vary. Nevertheless, hypogammaglobulinemia is typically confirmed if the serum IgG levels fall below 400 mg/dl. Hypogammaglobulinemia may be classified as [2]:

• Mild (IgG < 650 mg/dL)
• Moderate (IgG < 400 mg/dL)
• Severe (IgG < 200 mg/dL)

Several factors determine the occurrence, severity, and duration of hypogammaglobulinemia and infections. These include:

• Product type
• Age of the patient
• IgG levels before starting CAR-T therapy
• Use of chemotherapy during the CAR-T cell manufacturing period (the period between T cell collection and reinfusion of modified T cells)
• Type of cancer being treated

Understanding the Mechanism of CAR-T Therapy-Related Hypogammaglobulinemia

CAR-T therapy works by identifying and attacking cancer cells. It does so by identifying a specific protein on the surface of the B cells, which produce infection-fighting molecules called antibodies or immunoglobulins. 

Sometimes, CAR-T cells fail to differentiate cancerous B cells from healthy B cells. Consequently, they destroy both cancerous and normal B cells, leading to a low level of immunoglobulins. 

When To Use IVIG for CAR-T Therapy-Related Hypogammaglobulinemia

IVIG is often used after CAR-T therapy to reduce infection risk and manage hypogammaglobulinemia. However, this practice lacks standardization. 

Most experts agree that IVIG for CAR-T therapy-related hypogammaglobulinemia should be considered for patients with [1]:

• IgG ≤ 400 mg/dl within the first 90 days after starting treatment, especially if they get serious or recurrent bacterial infections. After 90 days, IVIG may be stopped if the patient has no infection. 
• IgG between 400 and 600 mg/dl who are having recurrent or serious infections. 
• IgG > 600 mg/dl, but are experiencing recurrent or serious infections, and blood tests show extremely low levels of specific antibodies.

IVIG for CAR-T Therapy-Related Hypogammaglobulinemia in Children

IVIG treatment should be considered for children with IgG below 400 mg/dl.

The usual dosage of IVIG for children of all ages is 0.5 g/kg monthly until the IgG level reaches the value considered normal for the child’s age. IVIG therapy should be started 30 days after CAR T-cell infusion. 

For those with IgG between 400 and 600 mg/dl, IVIG therapy should be considered every 3 to 4 weeks to maintain appropriate immunoglobulin levels.

For children younger than 10 years, IVIG therapy should be considered if the IgG level is equal to or less than 800 mg/dl [1].

Some health experts recommend IVIG every 3 to 4 weeks, as it may be superior to using IVIG as needed. 

IVIG for CAR-T Therapy-Related Hypogammaglobulinemia: What Are the Benefits?

IVIG has been associated with a myriad of benefits in patients receiving CAR-T cell therapy, such as [3]:

• A lower rate of infections
• Improvement in ongoing infections

IVIG may also be used to treat potentially fatal neurotoxicity associated with CAR-T therapy [4].

Frequently Asked Questions

1. Does IVIG treat hypogammaglobulinemia?

Yes, IVIG treats hypogammaglobulinemia by replacing antibodies obtained from donors. That way, IVIG helps prevent infections in individuals who have developed hypogammaglobulinemia secondary to a cancer treatment called CAR-T therapy. 

2. Is CAR-T better than chemo?

CAR-T cell therapy was superior to chemotherapy in improving survival and was associated with a higher rate of remission among patients with treatment-resistant acute lymphoblastic leukemia. This is according to a 2018 comparative study published in the Annals of Hematology [5].

3. What are the long-term side effects of CAR-T cell therapy?

The long-term side effects of CAR-T cell therapy can include:

• Low levels of red blood cells, white blood cells, or platelets in the blood
• Late infections
• Hypogammaglobulinemia 
• Neurocognitive deficits (impaired memory, attention, or thinking)

4. What is the death rate among patients receiving CAR-T cell therapy?

According to a 2024 study published in Nature, CAR-T therapy-related side effects were responsible for about 11% of total nonrelapse deaths [6].

5. What is B-cell aplasia?

B-cell aplasia is when the blood levels of B cells (a type of white blood cell) drop too low. It happens when CAR-T cells mistakenly attack and kill healthy B cells in the body.